Diisopropylamine → 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester

Temperature

-78 °C

A solution of diisopropylamine (0.55 mL, 3.94 mmol) in dry tetrahydrofuran (10 mL) was cooled to −78° C. under argon and was then treated with a 2.5M solution of n-butyllithium in hexanes (1.51 mL, 3.78 mmol). The reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (0.72 g, 3.15 mmol) in dry tetrahydrofuran (3.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.2 mL). The reaction mixture turned gold in color and was allowed to stir at −78° C. for 1 h. The reaction mixture was then treated with a solution of trifluoromethanesulfonic acid (R)-tetrahydro-furan-2-yl methyl ester (0.959 g, 4.10 mmol) in dry tetrahydrofuran (2 mL). The reaction mixture was allowed to warm to 25° C., where it was stirred for 52 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (25 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 9/1 hexanes/ethyl acetate eluted to 85/15 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (0.519 g, 52%) as a pale yellow oil: [α]23589=−19.02° (c=0.51, chloroform); EI-HRMS m/e calcd for C15H19ClO3S (M+) 314.0743, found 314.0743.

1. stirringto stir at −78° C. for 1 h
2. temperatureto warm to 25° C.
3. stirringwhere it was stirred for 52 h
4. customThe reaction mixture was quenched with a saturated aqueous ammonium chloride solution (25 mL)
5. concentrationconcentrated in vacuo
6. customto remove tetrahydrofuran
7. extractionThe aqueous residue was extracted with ethyl acetate (3×50 mL)
8. dry with materialThe combined organic extracts were dried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. washFlash chromatography (Merck Silica gel 60, 230–400 mesh, 9/1 hexanes/ethyl acetate eluted to 85/15 hexanes/ethyl acetate)

ORD record

ord-ac6c59d5901f46a590dafa2d99fd7ca9

Source dataset

uspto-grants-2006_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07105671B2